DESCRIPTION: (Applicant's Description) This proposal entitled "Phase I Clinical Trials of Anti-cancer Agents," which was prepared in response to RFA No. CA-97-001, requests support to pursue phase 1, pharmacological, and relevant translational laboratory studies of new anti-cancer agents developed under the auspices of the National Cancer Institute. The greatest therapeutic impacts on clinical oncology to date have resulted from the introduction of novel and their subsequent optimization in clinical practice with respect to dosing scheduling, sequencing, and use of combination regimens. Phase I studies represent a crucial step in the introduction of new anti-cancer agents, and the reliability of clinical and supportive laboratory data may significantly impact the subsequent development of new therapies. The overall objective of this proposal is to perform phase I studies of i n v estigational anti-cancer agents using interdigitated clinical, pharmacological, and laboratory strategies to optimize and facilitate the subsequent development of an array of new therapies. The proposal will demonstrate immense prior experience, success, and commitment of both investigators and institution to comprehensive drug development which involves the concurrent clinical, pharmacological, and basic laboratory elements. The specific aims of the proposal involve discerning both t r a d itional phase I endpoints (e.g., maximally tolerated doses and characterization of toxicity) and relevant biological and endpoints (e.g., minimally effective dose(s) in which relevant biological activity plateaus) of investigational agents. The latter is particularly important in view of the expectations that many novel anti-cancer agents may not have clear classical toxicological endpoints and the prospects for clinical utility may not be known until further evaluations have been completed. Therefore, other specific aims, including the assessment of relevant biological activity at the subcellular target, as well as pharmacological and pharmacological and pharmacodynamic behavior of the new agents, are of utmost importance in order to ultimately optimize both the therapeutic index and the development of new anti-cancer agents.